Article Figures & Data
Figures
- Figure 1.
Effect of the combination of paclitaxel (PTX) and ivermectin on cell viability in A549 cells. (A) A549 cells were incubated with PTX (0.001 μM) or ivermectin (3 μM), or the combination for 72 h. The anti-proliferative effect of the combination treatment was increased relative to PTX or ivermectin alone. *p<0.001, **p=0.008, and ***p=0.006 by one-way ANOVA followed by Tukey-Kramer’s test. (B) Apoptosis assay performed using an Annexin V-FITC Apoptosis Detection Kit. The percentages of apoptotic cells were higher with combination treatment. *p=0.002 and **p=0.001 by one-way ANOVA followed by Tukey–Kramer’s test.
- Figure 2.
P-glycoprotein (P-gp) down-regulation by ivermectin and the relevant signaling pathways. (A) A549 cells were incubated with ivermectin with the concentrations indicated. Ivermectin attenuated P-gp expression in a concentration dependent manner. (B) Ivermectin (3 μM) hindered the EGFR, ERK, Akt, and NF-
B phosphorylation in A549 cells and this was emphasized when co-treated with PTX (0.001 μM). (C) A549 cells were treated with either U0126 (10 μM) and SC75741 (10 μM), an MEK inhibitor that inhibits ERK activity and an NF-B inhibitor, respectively, for 72 h. These inhibitors attenuated P-gp expression. - Figure 3.
Effect of elacridar and tariquidar on cell viability in A549 cells treated with paclitaxel (PTX). A549 cells were incubated with PTX in combination with either elacridar (0.5 μM) (A) or tariquidar (1 μM) (B) for 72 h. Elacridar partially accelerated the effect of PTX; however, tariquidar had no effect on cell viability. *p=0.04, **p=0.008 compared to control cells.
- Figure 4.
P-glycoprotein (P-gp) up-regulation is implicated in acquired resistance to paclitaxel (PTX) in A549 cells. (A) MTS assays showing that A549 cells exposed to PTX for 16 weeks in a step-wise method developed a PTX-resistant phenotype. *p=0.027, **p=0.004, and ***p=0.006 compared to control cells. (B) ABCB1 mRNA expression was up-regulated in A549/PTXR cells compared with parental A549 cells, from 1.0 to 82.24. *p<0.001 by Student’s t-test. (C) Intracellular PTX concentration was determined using LC-MS/MS method both in parental A549 and A549/PTXR cells after cultured for 72 h. *p<0.001 by Student’s t-test. A549/PTXR; PTX-resistant A549 cells.
- Figure 5.
Effect of ABCB1 over-expression on paclitaxel (PTX)-induced cell death. (A) The structure of the final construct in pAAVS1-ABCB1 donor vector. The positions of binding sites of primers for genotyping the AAVS1 locus, are also indicated. (B) The representative data of genotyping of the AAVS1 locus by qRT-PCR with AAVS1_Geno primers. (C-E) Parental and ABCB1 over-expressing A549 cells were treated with PTX and the cell viability was assessed. ABCB1 over-expression exhibited PTX-resistant phenotype. *p<0.05 compared to parental cells.
- Figure 6.
Effect of ivermectin on P-glycoprotein (P-gp) expression induced by paclitaxel (PTX) long-term exposure. (A) A549 cells were cultured with ivermectin in a constant concentration (3 μM) during the induction of PTX-resistance. Ivermectin treatment almost completely abolished P-gp induction. (B) MTS assays showed that A549 cells co-cultured with ivermectin during the establishment of PTX-resistant cells were kept significantly sensitive to PTX at every time point examined until 16 weeks (wks). *p<0.05 when compared to A549 cells cultured with PTX alone. (C) A549 cells cultured with PTX using a step-wise method, with or without ivermectin, were treated with PTX (0.001 μM) for 72 h. Then, intracellular concentration of PTX was measured by the LC-MS/MS method. Intracellular PTX concentration significantly increased with ivermectin co-treatment. *p=0.006 by Student’s t-test. (D) Ivermectin inhibited the EGFR, ERK, Akt, and NF-
B phosphorylation in A549/PTXR cells. A549/PTXR; PTX-resistant A549 cells.
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